Project Summary Smoking cessation is associated with significant increases in consumption of palatable food and body weight, which negate many of the health benefits conferred by smoking abstinence. Indeed, individuals who successfully quit smoking gain 7-22 pounds of body weight, which, in turn, contributes to increased risk of obesity, diabetes type II, hypertension and other comorbidities. Moreover, post-cessation weight gain is often cited as the primary reason for continued smoking and smoking relapse in both men and women. Unfortunately, existing treatments for post-cessation weight gain are ineffective. Despite the public health significance of post-cessation weight gain, the neurobiological mechanisms underlying the relationships between smoking, food intake, and body weight regulation are poorly defined. Therefore, optimizing the health benefits of smoking cessation requires greater understanding of the neural mechanisms mediating nicotine withdrawal-induced hyperphagia in order to prevent weight gain and relapse during smoking abstinence. With this in mind, we have developed a rodent model of withdrawal-induced hyperphagia and body weight gain following voluntary nicotine taking. Our exciting preliminary data indicate that systemic administration of a glucagon-like peptide-1 (GLP-1) receptor agonist is sufficient to attenuate nicotine-seeking behavior during abstinence following nicotine self-administration. These results highlight, for the first time, a novel role for GLP-1 receptors in an animal model of smoking relapse and suggest that increased GLP-1 signaling may reduce other withdrawal-induced phenotypes including hyperphagia. We will extend our preliminary findings to female rats and expand upon them in both sexes to screen the efficacy of two different GLP-1 receptor agonists in attenuating nicotine seeking, hyperphagia and weight gain during nicotine abstinence (Aim 1). Our previous studies have shown that GLP-1 receptor agonists reduce intake of palatable food in drug-nave rodents by activating GLP-1 receptors expressed in brain regions known to regulate food reward and drug-seeking behavior, including the ventral tegmental area (VTA) and lateral dorsal tegmental area (LDTg). Since the neural circuits and mechanisms regulating hedonic feeding and drug seeking overlap, to a degree, these results support the hypothesis that activation of central GLP-1 receptors attenuates nicotine withdrawal-induced behavioral responses. Therefore, we will infuse GLP-1 receptor agonists directly into the VTA and LDTg during nicotine abstinence to determine if activation of discrete populations of central GLP-1 receptors is sufficient to attenuate nicotine seeking and hyperphagia during withdrawal (Aim 2). These experiments will provide the first insights into the neuroendocrine mechanisms underlying nicotine seeking, hyperphagia and weight gain during nicotine abstinence. Findings from these studies will have an immediate translational impact, as they will support re-purposing GLP-1 receptor agonists, which are FDA- approved for treating diabetes type II and obesity, for preventing smoking relapse and post-cessation weight gain.